Substituted 9-lower alkylacridine-4-carboxylic acids

ABSTRACT

THE COMPOUNDS ARE SUBSTITUTED 9-LOWER ALKYLACRIDINE4-CARBOXYLIC ACIDS HAVING ANTI-ARTHRITIC, ANTI-INFLAMMATORY, ANTIPYRETIC, ANALGESIC, ANTIVIRAL AND IMMUNOSUPPRESSANT ACTIVITY.

United States Patent US. Cl. 260-479 R 6 Claims ABSTRACT OF THE DISCLOSURE The compounds are substituted 9-lower alkylacridine- 4-carboxylic acids having anti-arthritic, anti-inflammatory, antipyretic, analgesic, antiviral and immunosuppressant activity.

This invention relates to new substituted acridines having pharmacological activity, in particular having antiarthritic, anti-inflammatory, antipyretic, analgesic, antiviral and immunosuppressant activity.

The compounds of this invention are represented by the following formula:

FORMULA I CR3 in which:

R; is trifluoromethyl, halo, sulfamoyl, N-methylsulfamoyl,

N,N dimethylsulfamoyl, methylsulfinyl, trifluoromethylsulfinyl, methylsulfonyl or trifluoromethylsulfonyl;

3,686,180 Patented Aug. 22, I972 Advantageous compounds of this invention are represented by Formula I in which R is trifluoromethyl, halo, trifluoromethylsulfinyl or trifluoromethylsulfonyl, R is methyl or ethyl and R is hydroxy.

A particularly advantageous compound of this invention is represented by Formula I in which R, is trifluoromethyl in the 6-position, R is methyl and R is hydroxy, said compound being 9-methyl-6-trifluoromethylacridine- 4-carboxylic acid.

The pharmaceutically acceptable salt derivatives of compounds of Formula I, also included in this invention, are salts of the carboxylic acid compounds of Formula I formed with organic or inorganic bases and pharmaceutically acceptable acid addition of quaternary ammonium salts of compounds of Formula I when the compounds have a basic center, that is when R is di-lower alkylamino-lower .alkoxy. Exemplary of the carboxylic acid salts are ammonium and alkali metal salts such as potassium or sodium salts. The acid addition salts are formed with acids such as hydrochloric, sulfuric, sulfamic, ethanedisulfonic, maleic, hydrobromic or phosphoric acids and the quaternary salts are formed with a quaternizing compound, for example, lower alkyl chloride, bromide or iodide, benzyl chloride, ethyl tosylate or methyl sulfate. The salt derivatives are prepared by Well known standard procedures. For example, the salts of the carboxylic acid compounds are prepared by reacting the acid compound with an equivalent amount of base in aqueous miscible solvent with isolation of the salt by concentration and cooling or with an excess of the base in an aqueous immiscible solvent with the salt separating directly. The acid addition salts and the quaternary ammonium salts are prepared by reacting the basic compound with an acid or quaternizing compound in suitable solvent.

The compounds of this invention are prepared by the following procedure:

R 1 .5 O R! 'l' x R1 N NH! H l COOR4 000R;

R R R: I l 5:0

on, coon H COOH R is alkyl having 1 to 6 carbon atoms; The terms R and R are as defined above; R is lower R is hydroxy, lower alkoxy, di-lower alkylaminolower alkoxy or NR'R" and R and R" are hydrogen or lower alkyl alkyl; R is lower alkoxy, di-lower alkylamino-lower alkoxy or NR'R"; R and R are as defined above and X is halo, preferably chloro or bromo.

According to the above procedure, a 2-lower alkanoylaniline is reacted with a lower alkyl Z-halobenzoate. The reaction is carried out in the presence of a copper catalyst, such as copper powder or copper-bronze, and an alkali metal carbonate, for example sodium carbonate, in a solvent such as nitrobenzene or dimethylformamide. The reaction is carried out at elevated temperature, preferably at reflux temperature. The resulting substituted 2'- lower alkanoyldiphenylamine-Z-carboxylic acid ester is bydrolyzed to the free carboxylic acid by treating with an alkali metal carbonate, for example sodium carbonate, in aqueous lower alkanol solution. The substituted 2'-lower alkanoyldiphenylamine-2-carboxylic acid is cyclized by treating with acid, for example a mixture of acetic acid and sulfuric acid, at elevated temptrature to give the substituted 9-lower alkylacridine-4-carboxylic acids of this invention.

The compounds of Formula I in which R is lower alkoxy, di-lower alkylamino-lower alkoxy or NRR" are prepared from the corresponding carboxylic acid compounds, i.e. the corresponding compounds of Formula I in which R is hydroxy, by standard procedures. For example, the carboxylic acid group may be converted to the carbonyl chloride by reacting with thionyl chloride or phosphorus trichloride and the carbonyl chloride is reacted with the appropriate lower alkanol, di-lower alkylamino-lower alkanol or amines (HNRR") to give the corresponding carboxylic acid derivatives of this invention. Also, the esters may be prepared by standard esterification procedures.

The substituted 2-lower alkanoylaniline starting materials of the above procedure are prepared by the following known procedures:

The terms R and R are as defined above and X and X are chloro or bromo.

According to procedure I above, the substituted 2- lower alkanoylaniline starting materials are prepared by reacting a 2-haloaniline with cuprous cyanide, or reacting a 2-halo-nitrobenzene with cuprous cyanide and reducing the nitro group, to give the 2-aminobenzonitrile and reacting the 2-aminobenzonitrile with a lower alkyl magnesium halide, R MgX', in an ethereal solution and then treating with an acid such as glacial acetic acid or dilute hydrochloric acid.

According to procedure II above, an anthranilic acid is converted to the acid chloride by treating with thionyl chloride or phosphorus trichloride and then the anthranilic acid chloride is reacted with a di-lower alkylcadmium compound to give the 2-lower alkanoylaniline starting materials.

The compounds of this invention are administered internally either parenterally or preferably orally in an amount to induce the desired biological activity. Most conveniently, the compound is combined with a standard pharmaceutical carrier and administered orally as a capsule, tablet, troche or liquid or parenterally as a sterile suspension.

The anti-arthritic activity of the compounds of this invention is demonstrated by ability to inhibit adjuvantinduced polyarthritis in rats. The compounds of this invention decrease the inflamed hind leg volumes in experimental rats at oral doses of 6.25 to 100 mg./kg./day.

The terms lower alkyl and lower alkoxy where used herein denote groups having 1 to 4 carbon atoms and halo denotes chloro, bromo or fiuoro.

4 The following examples are not limiting but are illustrative of the compounds of this invention and processes for their preparation.

EXAMPLE 1 Cuprous cyanide (234 g.) is added slowly with stirring to 213 g. of dry pyridine. The mixture which solidifies is heated until a homogeneous melt is obtained (ll0 C.), then heating is continued until the temperature reaches C. Any excess pyridine is boiled off. The temperature is then alloyed to drop to approximately 110 C. and then with stirring 487 g. of 2-bromo-5-trifiuoromethylaniline is added slowly. The mixture is gradually heated with stirring and stirred at -170 C. for 75 minutes. The mixture is then cooled to about 90 C. and a concentrated solution of sodium cyanide (750 g. in 750 ml. of water) is added with stirring. The resulting mixture is stirred for several minutes, then 250 ml. of benzene is added and the stirring is continued for one hour. The benzene layer is separated from the aqueous layer, washed with three portions of water and dried. The benzene is removed in vacuo on a steam bath and the residue is distilled. The distillate which solidifies is melted and poured into hexane with stirring and cooling. Filtering off and air drying the solid material gives 2-amino-4-trifluoromethylbenzonitrile, M.P. 87-89 C.

A solution of 60.5 g. of 2-amino-4-trifiuoromethylbenzonitrile in 800 ml. of dry tetrahydrofuran is cooled to 0 C. as 50 ml. of a 3 M solution of methylmagnesium bromide in ether is added dropwise with stirring. The suspension is stirred at room temperature for 24 hours, then ether is removed by distillation and the residual mixture allowed to stir at room temperature another 48 hours. The resulting solution is stirred into a mixture of 200 ml. of glacial acetic acid and 500 ml. of ice and water and the organic material removed by ether extraction. The extract is washed with water and with aqueous sodium carbonate solution, then dried and concentrated under reduced pressure. The residue is steam distilled and the distillate crystallized from 1:1 ethanol: water to give 2-amino-4-trifluoromethylacetophenone, M.P. 79-80 C.

A mixture of 5.08 g. of 2-amino-4-trifluoromethylacetophenone, 5.0 g. of methyl 2-chlorobenzoate, 0.2 g. of copper-bronze and 10 g. of anhydrous sodium carbonate in 30 ml. of nitrobenzene is heated at reflux with stirring for three hours. The cooled solution is filtered. The filtrate is steam distilled and the residue is cooled and extracted with ether. The extracts are dried and concentrated under reduced pressure. Vacuum sublimation of the residue and then recrystallizing from aqueous ethanol gives the methyl ester of 2-acetyl-5-trifluoromethyldiphenylamine-2'-carboxy1ic acid. The ester is refluxed with 2.5% aqueous sodium carbonate solution in 1:1 aqueous alcohol to give, after neutralizing with dilute hydrochloric acid, extracting with ether and then removing the ether from the extracts in vacuo, Z-acetyl-S- trifluoromethyldiphenylamine-2' carboxylic acid; M.P. 194-1945 C. (recrystallized from aqueous alcohol).

A solution of 21 g. of 2-acetyl-5-trifluoromethyldiphenylamine-2'-carboxylic acid in a mixture of 85 ml. of acetic acid and 15 ml. of sulfuric is heated at steam bath temperature for two hours. The mixture is cooled, then poured into a liter of ice and water. The resulting mixture is neutralized to pH 4 with aqueous sodium hydroxide solution. The solid which separates is filtered 01f, dried and recrystallized from isopropanol to give 9- methyl-6-trifiuoromethylacridine-4-carboxylic acid, M.P. 240-241 C.

EXAMPLE 2 By the procedure of Example 1 using 4.2 g. of 2-amino- 4-chloroacetophenone in place of 2-amino-4-trifluoromethylacetophenone, the product is 6-chloro-9-methylacridine-4-carboxylic acid.

EXAMPLE 3 By the procedure of Example 1 using in place of 2- bromo-S-trifluoromethylaniline, the following:

2-chloro-S-trifluoromethylsulfonylaniline 2-bromo-4-trifluoromethylsulfonylaniline 3-amino-4-bromobenzenesulfonamide 3-amino-4-chloro-N-methylbenzenesulfonamide 3-amino-4-chloro-N,N-dimethylbcnzenesulfonamide the products are, respectively:

9-methyl-7-trifluoromethylsulfonylacridine-4-carboxylic acid 9-methyl-6-trifluoromethylsulfonylacridine-4-carboxylic acid 9-methyl-6-sulfamoylacridine-4-carboxylic acid 9-methyl-6-(N-methylsulfamoyl)acridine-4-carboxylic acid 9-methyl-6-(N,N-dimethylsulfamoyl)acridine-4-carboxylic acid.

EXAMPLE 4 2 bromo 5 trifluoromethylsulfinyl-nitrobenzene is reacted with cuprous cyanide and pyridine according to the procedure of Example 1 to give 2-nitro-4-trifluoromethylsulfinylbenzonitrile. The nitro compound is dissolved in acetic acid, the solution is heated at 60 C., zinc dust is added portionwise, and the mixture is heated at 70 C. for one hour. The hot solution is filtered through a layer of kieselguhr and the filtrate is concentrated in vacuo to about one-third volume and diluted with two to three volumes of water. The oily separation is extracted into benzene, the extracts dried and concentrated and the residue distilled in vacuo to give 2-amino-4-trifluoromethylsulfinylbenzonitrile.

Using 2 amino 4-trifluoromethylsulfinylbenzonitrile in place of 2-amino-4-trifiuoromethylbenzonitrile in the procedure of Example 1 gives 9-methyl-6-trifluoromethylsulfinylacridine-4-carboxylic acid.

EXAMPLE 5 2-chloro-5-methylthionitrobenzene is reduced with zincacetic acid by the procedure of Example 4 to give 2- chloro-S-methylthi-arfiline.

Using 2-chloro-5-methylthioaniline in place of 2- bromo-5-trifluoromethylaniline in the procedure of Example 1 gives 9-methyl-6-methylthioacridine-4-carboxylic acid.

A solution of m-chloroperbenzoic acid in chloroform (5%) is added rapidly, dropwise to a cooled solution of 9-methyl-6 methylthioacridine 4 carboxylic acid in chloroform. After the addition is complete, the mixture is stirred an additional three hours at room temperature and then filtered to give 9-methyl-6-methylsulfinylacridinelcarboxylic acid.

EXAMPLE 6 Using 2-chloro-S-methylsulfonylaniline in place of 2- bromo-S-trifluoromethylaniline in the procedure of Example l, the product is 9-methyl-6-methylsulfonylacridine-4-carboxylic acid.

EXAMPLE 7 Bythe procedure of Example 1, 2-amino4-trifluoromethylbenzonitrile is reacted with ethylmagnesium bromide to give 2-amino-4-trifluoromethylphenyl ethyl ketone. Using 2-amino4-trifluoromethylphenyl ethyl ketone in place of 2-amino-4-trifluoromethylaoetophenone in the procedure of Example 1, the product is 9-ethyl- 6-trifluoromethylacridine-4-carboxylic acid.

By the same procedure using propylmagnesium bromide in place of ethylmagnesium bromide, the product is 9-propyl-6-trifluoromethylacridine-4-carboxylic acid.

Using butylmagnesium bromide in place of ethylmagnesium bromide, the product is 9-butyl-6-trifluoromethylacridine-4-carboxylic acid.

6 Similarly, using hexylmagnesium bromide in place of ethylmagnesium bromide, the product is 9-hexyl-6-trifluoromethylacridine-4-carboxylic acid.

EXAMPLE 8 EXAMPLE 9 An ether solution containing 1.0 g. of 9-methyl-6-trifluoromethylacridine-4-carbonyl chloride (prepared as in Example 8) is reacted with an excess of ammonia to give, after concentrating in vacuo, 9-methyl-6-trifiuoromethylacridine-4-carboxamide.

Reacting 9 methyl-6-trifluoromethyl-4-carbonyl chloride with dimethylamine in ether gives N,N-dimethyl-9- methyl-G-trifiuoromethylacridine-4-carboxamide. Heating this product with methyl iodide gives the methiodide.

Similarly, using dibutylamine in place of dimethylamine, the product is N,N-dibutyl-9-methyl-6-trifiuoromethyl-4- carboxamide. Reacting this product with an excess of sulfuric acid gives the sulfate salt.

EXAMPLE 10 An excess of diethylaminoethyl chloride is added slowly to a stirred, heated solution of 5 g. of 9-methyl-6-trifluoromethyl-acridine-4-carboxylic acid (prepared as in Example 1) in isopropanol. The mixture is heated at reflux for several hours, then concentrated to give diethylaminoethyl 9 methyl-6-trifluoromethylacridine-4-carboxylate hydrochloride. An ether-ethyl acetate solution of this compound is neutralized with aqueous sodium carbonate solution, extracted with ether and the ether extract concentrated in vacuo to give the free base. The free base is converted to other salts by reacting with excess amounts of the appropriate acid.

EXAMPLE 11 9-methyl-fi-trifluoromethylacridine 4 carboxylic acid (prepared as in Example 1) in acetonitrile-ether is stirred with an excess of sodium methoxide to give the sodium salt.

Similarly, 9-methyl 6 trifluoromethylacridine-4-carboxylic acid in acetonitrile-ether is stirred with an excess of ammonia to give the ammonium salt.

What is claimed is:

1. A compound of the formula:

I C0 B3 in which:

R is trifluoromethyl, halo, sulfarnoyl, N-methylsulfamoyL N,N-dimethylsulfamoyl, methylsulfinyl, trifluoromethylsulfonyl;

R is alkyl having 1 to 6 carbon atoms;

R is hydroxy, lower alkoxy, di-lower alkylamino-lower alkoxy or NR'R" and R and R" are hydrogen or lower alkyl or, when R is hydroxy, ammonium or alkali metal salts thereof or,

when R is di-lower alkylamino-lower alkoxy, pharmaceutically acceptable acid addition salts thereof, said lower alkyl and lower alkoxy groups having 1 to 4 carbon atoms.

2. A compound according to claim 1 in which R is trifluoromethyl, halo, trifiuoromethylsulfinyl or trifluoromethylsulfonyl.

3. A compound according to claim 1 in which R is trifluorornethyl, halo, trifluoromethylsulfinyl or trifluoromethylsulfonyl and R is hydroxy.

4. A compound according to claim 1 in which R is trifluoromethyl, halo, trifluoromethylsulfinyl or trifluoromethylsulfonyl, R is methyl or ethyl and R is hydroxy.

5. A compound according to claim 1 in which R is trifluoromethyl.

6. The compound according to claim 1 in which R is trifluoromethyl in the 6-position, R is methyl and R is hydroxy.

References Cited UNITED STATES PATENTS 3,033,866 5/ 1962 Saggiomo 260279 3,043,842 7/1962 Craig 260279 X 3,072,485 1/1963 Reynolds 260279 X 3,539,574 11/1970 Sheehan et al 260279 3,615,416 10/1971 Fox 260279 R 3,519,424 7/ 1970 Reynolds et al. 260279 R FOREIGN PATENTS 610,581 10/1948 Great Britain 260279 DONALD G. DAUS, Primary Examiner US. Cl. X.R.

260465 E, 465 F, 465 G, 469, 471 R, 519, 575; 424 257 mg? I UNITED STATES PATENT OFFICE 0 CERTIFICATE O GORREC'HON Invent ff) Blain'MQ'Su tton It is: certified that error appearsin the above-identified potent and that said Letters Patent are hereby corrected as shown below:

73 011mm 1-, lines 26-27', R v should be R Y Column 6, line 70, reading sillfQnylf Should read Su finyl, methylsulf y trifluorqmethylsulmyl;

Signed and sealed thismiloth day of December 1972.

Attesfi:

EDWARQI LFL TCHER R. I t 'RUBERL' GO'lTSC'I-IALK Attestlng Officer v v Commissioner of Patents 

